Chronic Renal Insufficiency (CRI) often progresses to End Stage Renal Disease (ESRD), with an increased prevalence and fatality from Cardiovascular Disease (CVD). We hypothesize that CRI progression is explained by clinical, genetic and humoral factors which also contribute to development and progression of CVD in subjects with CRI. To address this hypothesis we propose two specific Aims: #1) To determine risk factors for the progression of CRI, including the dependence of progression upon clinical, genetic and humoral factors, and #2) To determine the role of clinical, genetic and humoral risk factors for the development and progression of CVD in subjects with CRI. Detailed plans are presented for how we will identify and access eligible subjects via an existing and functioning database at our Center. A query of this database with the creatinine criteria of > or = 1.7 mg/dl for men and > or = 1.4 mg/dl for women (upon which we imposed the additional constraint of requiring two creatinine values at least 90 days apart) identified more than 4,000 eligible subjects. Using the database results a pilot recruitment study was undertaken. We contacted 33 representative subjects from two Primary Care practices. Fourteen of 33 subjects (42%; 95% CI 25-61%) gave an unqualified 'yes' they would participate in the protocol we propose in this application, and another 4 subjects indicated they would 'probably' participate after discussing it further with their PCP. Thus, we project an adequate number of willing subjects already identified within our Health System. Next, we describe methods for identifying and contacting under-served subjects with CRI through our ED and student-run health clinics. For Aim #l we present an enrollment strategy assuring adequate gender, ethnicity and renal disease representation. In Aim #1 we provide detailed nuclear GFR methods and endpoints for CRI progression, along with historical, physical exam, laboratory, quality-of-life and imaging procedures that serve the primary and secondary goals of the RFA. We propose measurement of specific inflammatory, growth, cytokine, lipoprotein, oxidative stress, calcitropic and hemodynamic factors showing their rationale for inclusion and mechanisms by which they contribute to CRI and CVD. For Aim #2 we present specific CVD definitions, and an imaging strategy that provides three measures of CVD prevalence (carotid IMT thickness, echocardiogram and EBCT) and two measures of CVD progression (carotid IMT thickness, echocardiogram). The data collected on the proposed clinical, genetic and humoral factors at our experienced Clinical Center will contribute substantially to the understanding of CRI, and CVD in subjects with CRI..